chr14-50910056-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B.

-21

BP4_StrongBP6_Very_StrongBP7BA1

The NM_002863.5(PYGL):c.2016C>T(p.Thr672Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 1,613,832 control chromosomes in the GnomAD database, including 19,395 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 4367 hom., cov: 33)

Exomes 𝑓: 0.13 ( 15028 hom. )

Consequence

PYGL
NM_002863.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -4.01

Publications

15 publications found

Variant links:

Genes affected

PYGL (HGNC:9725): (glycogen phosphorylase L) This gene encodes a homodimeric protein that catalyses the cleavage of alpha-1,4-glucosidic bonds to release glucose-1-phosphate from liver glycogen stores. This protein switches from inactive phosphorylase B to active phosphorylase A by phosphorylation of serine residue 15. Activity of this enzyme is further regulated by multiple allosteric effectors and hormonal controls. Humans have three glycogen phosphorylase genes that encode distinct isozymes that are primarily expressed in liver, brain and muscle, respectively. The liver isozyme serves the glycemic demands of the body in general while the brain and muscle isozymes supply just those tissues. In glycogen storage disease type VI, also known as Hers disease, mutations in liver glycogen phosphorylase inhibit the conversion of glycogen to glucose and results in moderate hypoglycemia, mild ketosis, growth retardation and hepatomegaly. Alternative splicing results in multiple transcript variants encoding different isoforms.[provided by RefSeq, Feb 2011]

PYGL Gene-Disease associations (from GenCC):

glycogen storage disease VI
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Genomics England PanelApp, Orphanet, Ambry Genetics

PYGL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 14-50910056-G-A is Benign according to our data. Variant chr14-50910056-G-A is described in ClinVar as [Benign]. Clinvar id is 258836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.01 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYGL	NM_002863.5 link	c.2016C>T	p.Thr672Thr	synonymous_variant	Exon 17 of 20	ENST00000216392.8	NP_002854.3	P06737-1
PYGL	NM_001163940.2 link	c.1914C>T	p.Thr638Thr	synonymous_variant	Exon 16 of 19		NP_001157412.1	P06737-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PYGL	ENST00000216392.8 link	c.2016C>T	p.Thr672Thr	synonymous_variant	Exon 17 of 20	1	NM_002863.5	ENSP00000216392.7	P06737-1
PYGL	ENST00000532462.5 link	c.2016C>T	p.Thr672Thr	synonymous_variant	Exon 17 of 20	1		ENSP00000431657.1	E9PK47
PYGL	ENST00000544180.6 link	c.1914C>T	p.Thr638Thr	synonymous_variant	Exon 16 of 19	2		ENSP00000443787.1	P06737-2
PYGL	ENST00000532107.2 link	n.189C>T		non_coding_transcript_exon_variant	Exon 2 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.205

AC:

31199

AN:

152002

Hom.:

4362

Cov.:

show subpopulations

Gnomad AFR

AF:

0.407

Gnomad AMI

AF:

0.123

Gnomad AMR

AF:

0.133

Gnomad ASJ

AF:

0.131

Gnomad EAS

AF:

0.108

Gnomad SAS

AF:

0.172

Gnomad FIN

AF:

0.130

Gnomad MID

AF:

0.155

Gnomad NFE

AF:

0.127

Gnomad OTH

AF:

0.169

GnomAD2 exomes

AF:

0.149

AC:

37481

AN:

251450

AF XY:

0.148

show subpopulations

Gnomad AFR exome

AF:

0.409

Gnomad AMR exome

AF:

0.0872

Gnomad ASJ exome

AF:

0.139

Gnomad EAS exome

AF:

0.107

Gnomad FIN exome

AF:

0.126

Gnomad NFE exome

AF:

0.133

Gnomad OTH exome

AF:

0.135

GnomAD4 exome

AF:

0.134

AC:

195900

AN:

1461712

Hom.:

15028

Cov.:

AF XY:

0.136

AC XY:

98607

AN XY:

727162

show subpopulations

African (AFR)

AF:

0.415

AC:

13906

AN:

33470

American (AMR)

AF:

0.0939

AC:

4200

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.137

AC:

3584

AN:

26134

East Asian (EAS)

AF:

0.148

AC:

5865

AN:

39698

South Asian (SAS)

AF:

0.189

AC:

16268

AN:

86244

European-Finnish (FIN)

AF:

0.127

AC:

6800

AN:

53420

Middle Eastern (MID)

AF:

0.156

AC:

901

AN:

5768

European-Non Finnish (NFE)

AF:

0.122

AC:

135809

AN:

1111868

Other (OTH)

AF:

0.142

AC:

8567

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

9856

19711

29567

39422

49278

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4980

9960

14940

19920

24900

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.205

AC:

31229

AN:

152120

Hom.:

4367

Cov.:

AF XY:

0.204

AC XY:

15137

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.407

AC:

16862

AN:

41466

American (AMR)

AF:

0.132

AC:

2023

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.131

AC:

456

AN:

3468

East Asian (EAS)

AF:

0.108

AC:

560

AN:

5180

South Asian (SAS)

AF:

0.172

AC:

827

AN:

4820

European-Finnish (FIN)

AF:

0.130

AC:

1373

AN:

10586

Middle Eastern (MID)

AF:

0.163

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.127

AC:

8615

AN:

68000

Other (OTH)

AF:

0.167

AC:

353

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1195

2390

3586

4781

5976

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

312

624

936

1248

1560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.156

Hom.:

8543

Bravo

AF:

0.209

Asia WGS

AF:

0.159

AC:

552

AN:

3478

EpiCase

AF:

0.123

EpiControl

AF:

0.129

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Apr 12, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 05, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Glycogen storage disease, type VI

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.0080

(source)

DANN

Benign

0.82

PhyloP100

-4.0

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over